The objective of this grant is to develop imaging agents for studying serotonin transporters (SERT) of the central nervous system (CNS) using positron emission tomography (PET). Changes in serotonergic neuronal function in the CNS occur in patients with major depression. A series of new antidepressants preferentially increase 5-HT (serotonin) transmission by inhibiting serotonin reuptake. These selective serotonin reuptake inhibitors (SSRIs) have revolutionized the management of depression for millions of patients, and they are now widely prescribed for treating various other mental disorders such as compulsive obsessive and social phobic disorders. The PET imaging agents to be tested in this project are critically important for studying binding sites of psychoactive drugs and monitoring the effectiveness of such drug treatment in the living human brain. In the past funding period we have prepared many fluorinated biphenylthiol derivatives with limited success. However, recently we found that changing the substitution at a different position of biphenylthiol appears to hold the key for improving the specific SERT binding (uptake and retention in the hypothalamus where SERT binding sites are highly concentrated) and more importantly for reducing the non-specific binding (in the cerebellum). In this renewal application three specific aims are proposed: 1) to synthesize and test a series of 18F labeled biphenylthiol derivatives as SERT ligands for PET imaging studies. 2) to perform in vivo biological evaluation of selectivity and kinetics of binding to SERT in the brain of rats. 3) to compare PET imaging agents proposed in this project and other SERT ligands labeled with 18F in non-human primates with the ultimate objective of identifying one or two final candidates suitable for human study. In vivo PET or SPECT imaging studies may provide an effective approach in estimating the drug occupancy of the target sites - SERT binding sites by the antidepressants used for treatment. Thus, imaging of SERT binding sites may open a small window allowing a direct measurement of drug action at the target sites in the brain. There is a compelling need to develop improved the PET imaging agents for studying this important target modulating the serotonin function in the brain. It is likely that 18F labeled tracers for imaging SERT can be prepared by regional radiopharmacies and distributed within any major metropolitan area. Thus, the imaging tool would be widely available to benefit a large number of patients. PUBLIC HEALTH RELEVANCE: Changes in serotonergic neuronal function in the brain occur in patients with major depression. The serotonin transporter imaging agents to be tested in this project are critically important for studying binding of antidepressants in the living human brain. The proposed tracers for imaging SERT can be prepared by regional radiopharmacies and distributed within any major metropolitan area benefiting a large number of patients undergoing antidepressant treatment.